The aromatic amine moiety is a structural component in a variety of many useful organic compounds. Such compounds are useful in their own right, or as intermediates in the preparation of, for example, dyes, herbicides, insecticides, and pharmaceuticals. Aromatic primary amines are of particular interest and may be converted though derivatization to a wide variety of derivatives, for example via alkylation (to form secondary or tertiary amines), acylation (to form amides) or sulfonylation (to form sulfonamides).
New methods of synthesizing aromatic primary amines are needed. Many of the classical methods of preparing such compounds suffer from problems such as requiring harsh reaction conditions and are therefore lacking compatibility with other functional groups or selectivity, or being of limited scope.
A well-known procedure for the synthesis of aromatic primary amines involves nitration of an aromatic ring with an electrophilic nitrating agent, followed by reduction of the resulting aromatic nitro compound. The usefulness of the procedure may be limited by the lack of selectivity or inappropriate selectivity of the nitrating agent (typically nitric acid). Selectivity requires the reagent to attack one C—H bond selectively in the presence of other C—H bonds in the compound and other reactive functionalities in the substrate. For example, in substrates containing an activating group—a group that donates electrons to the aromatic ring—a mixture of nitrated products may be obtained wherein the nitro group is introduced ortho and/or para to the activating group. Further, activated substrates (electron rich aromatic groups) may be over-nitrated to give di- or tri-nitro derivatives. The nitrating agents are powerful oxidants, and therefore not compatible with all substrates. In addition, in order to effect conversion to the primary amine, selective reduction of the nitro group must be achieved.
Other methods of synthesizing aromatic amines involve substitution of existing functional groups. For example, nucleophilic substitution reactions of electron-deficient aromatic compound is efficient for certain substrates. See Hattori, et al., Synthesis, 1994, 199; and Bunnett, Acc. Chem. Res., 1978, 11, 413. The usefulness of such reactions is generally limited to substrates that are activated to substitution via an SNAr mechanism, where an electron withdrawing group stabilizes the intermediate resulting from nucleophile addition to the position of the aromatic ring bearing a leaving group. A suitable electron withdrawing group disposed in a 1,2- or 1,4-position relative to the leaving group activates substrate to nucleophilic displacement by the SNAr mechanism by stabilizing the transition state to the intermediate in which the nucleophile is added to the aromatic ring. In suitable substrates, displacement can be achieved using an amine or ammonia as the nucleophile.
In nucleophilic substitution substrates that lack a suitable activating (i.e. electron-withdrawing) group, displacement of a leaving group can sometimes be achieved with powerfully basic anionic metal amides. However, rather than occurring via the SNAr addition-elimination mechanism, such displacements may occur via an elimination-addition mechanism proceeding via base-induced elimination of H—X (wherein X is the leaving group) to form an “aryne” intermediate, followed by addition of the amide to the C≡C bond of the aryne. Since the amide addition to the aryne may occur at either of the carbon atoms of the C≡C bond of the aryne, the amino group may be introduced either at the carbon at which the leaving group was located, or at an adjacent position (the latter being referred to as “cine substitution”). Thus, even if a substrate is compatible with the powerfully basic conditions for displacement with a metal amide, the substitution reaction may result in a mixture of products.
A very useful variation on the nucleophilic aromatic substitution reaction has been the use of organometallic catalysts in catalyzed cross-coupling reactions of substituted aromatic compounds with amino compounds. Such reactions typically involve an aromatic substrate having a halide or sulfonate leaving group reacted with an organic amine in the presence of an organometallic catalyst. The organometallic catalyst is typically a palladium catalyst comprising a phosphine ligand (usually a chelating phosphine ligand such as 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, or a sterically hindered monophosphine such as biphenyl-2-yldi-t-butylphosphine). The reaction is typically performed in the presence of a base such as sodium t-butoxide. Such reactions achieve an equivalent result to the nucleophilic displacement of the leaving group of the aromatic substrate with the amino compound. For references, see, e.g., J. Louie and J. F. Hartwig, Tetrahedron Lett., 1995, 36, 3609; A. S. Guram, et al., Angew. Chem, Int. Ed. Engl., 1995, 34, 1348; J. F. Hartwig, Synlett, 1997, 329; J. F. Hartwig, Pure Appl. Chem., 1999, 71, 1417-1423; S. L. MacNeil et al., Synlett, 1998, 419; J. F. Hartwig, Angew, Chem. Int. Ed. Engl., 1998, 37, 2046-2067; J. F. Hartwig, Acc. Chem. Res., 1998, 31, 852; J. P. Wolfe, et al., Acc. Chem. Res., 1998, 31, 805-818; B. H. Yang and S. L. Buchwald, J. Organomet. Chem., 1999, 576 (1-2), 125-146; S. L. Buch wald, Top. Curr. Chem., 2002, 219, 131-209; J. F. Hartwig, “Palladium-catalyzed amination of aryl halides and related reactions” in “Handbook of Organopalladium Chemistry for Organic Synthesis” by E.-i. Negishi, et al., Wiley-Interscience (2002), pp. 1051-1096; L. Jiang and S. L. Buchwald, “Palladium-Catalyzed Aromatic Carbon-Nitrogen Bond Formation” in “Metal-Catalyzed Cross-Coupling Reactions” by A. de Meijere, et al., Wiley-VCH (2004), pp. 699-760; U.S. Pat. No. 5,576,460; U.S. Pat. No. 5,977,361; and U.S. Pat. No. 6,235,938. The catalyzed amination reaction is believed to involve a catalytic cycle involving oxidative addition of the aromatic compound to a palladium (0) complex, ligand exchange wherein the leaving group of the aromatic compound is exchanged for the amine to form a palladium-nitrogen complex, followed by reductive elimination of the aromatic amine compound.
In spite of the advance represented by the catalyzed cross-coupling reaction of substituted aromatic compounds with amino compounds, a significant limitation of the process is that prior to the present invention, no method for directly cross-coupling ammonia or metal amides (containing an NH2− anion) with an aromatic compound to form aromatic primary amines has been reported. Such a method, if available, would be a very convenient method of preparing aromatic primary amines, particularly in view of the fact that ammonia is a very readily available, and cheap, bulk chemical.
Instead of using ammonia, previous syntheses of aromatic primary amines using the cross-coupling methodology have employed ammonia surrogates that require deprotection in order to give the primary amine. Such approaches thus give the primary amine only indirectly. Examples of references describing such approaches using ammonia surrogates are: S. Jaime-Figueroa, et al., Tetrahedron Lett. 1998, 39, 1313; G. Mann, et al., J. Am. Chem. Soc., 1998, 120, 827; J. P. Wolfe, et al., Tetrahedron Lett., 1997, 38, 6367; J. P. Wolfe, et al., J. Org. Chem., 2000, 65, 1158; G. A. Grasa, et al., J. Org. Chem., 2001, 66, 7729; S. Lee, et al., Org. Lett., 2001, 3, 2729; X. Huang, et al., Org. Lett., 2001, 3, 3417; J. Barluenga, et al., Angew. Chem., Int. Ed. Engl., 2004, 43, 343. Jaime-Figueroa, et al. (Tetrahedron Lett., 1998, 39, 1313-1316) described the use of allyl amines as ammonia equivalents in the cross-coupling methodology, in a process that required subsequent deallylation of the resulting allylamine to prepare the desired primary amine. Wolfe, et al. (Tetrahedron Lett., 1997, 38, 6368) described the use of benzophenone imine as an ammonia surrogate in cross-coupling reactions in which the cross-coupling proceeds initially to give an N-substituted benzophenone imine, which undergoes acid-catalyzed hydrolysis to give the desired aromatic primary amine. In another approach, lithium hexamethyldisilazide has been used in cross-coupling reactions, with the resulting aromatic N,N-bis(trimethylsilyl)amine yielding the aromatic primary amine upon hydrolysis. S. Lee, et al., Org. Lett., 2001, 3, 2729; X. Huang, et al., Org. Lett., 2001, 3, 3417.
In view of the disadvantages of traditional methods of synthesizing aromatic primary amines, and the convenience and efficiency of the transition-metal-catalyzed cross-coupling reactions to form amines, it would be very desirable to have available a process in which cross-coupling of ammonia or a metal amide could be used in a cross-coupling reaction to prepare primary amines directly, without having to use ammonia surrogates.
Such a reaction would be useful for the synthesis of a wide variety of compounds. Compounds that could be prepared by such a process include compounds that are useful, for example, as pharmaceuticals, agricultural products (e.g., herbicides, pesticides), organic materials such as anti-oxidants, or ligands for use in catalysts, as well as intermediates in the synthesis of such products.